Chemotherapy, metabolic pathway may affect CAR T-cell potential

Two critical factors – prior exposure to chemotherapy and a glycolytic metabolism – appear to degrade the potential of T cells to become chimeric antigen receptor–T cells.

Chemotherapy, especially with cyclophosphamide and doxorubicin, seems particularly toxic to T cells, damaging the mitochondria and decreasing the cells’ spare respiratory capacity – a measure of mitochondrial health, David Barrett, MD, said during a press briefing held in advance of the annual meeting of the American Association for Cancer Research.

Dr. David Barrett

Cells that relied primarily on glucose for fuel were much weaker and less able to withstand the chimeric antigen receptor (CAR) transformation and expansion process. Both of these characteristics were more common in cells from patients with solid tumors than in cells from patients with leukemia, said Dr. Barrett of the Children’s Hospital of Philadelphia.

These new findings may help explain why children with acute lymphoblastic leukemia (ALL) tend to respond so vigorously to CAR T treatment, and why T cells from patients with solid tumors simply don’t grow, or die soon after patient infusion, he said in an interview. They also suggest a benefit of harvesting T cells before any chemotherapy, a procedure Dr. Barrett and his colleagues have advocated.

“Based on these data we have altered our practice for T-cell therapy in high-risk leukemia patients. If we have a patient who may have a poor prognosis, we try to collect the cells early and store them before proceeding, because we know chemotherapy will progressively degrade them.”

There still is no successful CAR T-cell protocol for solid tumors, but Dr. Barrett said these findings eventually may help such patients, particularly if more advanced experiments in manipulating the cells’ metabolism prove successful.

He and his colleagues investigated why T cells from some patients result in a poor clinical product that either fails manufacture or does not proliferate in the patient. They examined T cells from 157 pediatric patients with a variety of cancers, including ALL, non-Hodgkin lymphoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, Wilms tumor, Hodgkin disease, chronic myelogenous leukemia, and Ewing sarcoma. The team obtained cells at diagnosis and after each cycle of chemotherapy.